Overexpression of peroxisome proliferator-activated receptor-alpha (PPARalpha)-regulated genes in liver in the absence of peroxisome proliferation in mice deficient in both L- and D-forms of enoyl-CoA hydratase/dehydrogenase enzymes of peroxisomal beta-oxidation system.

Peroxisomal beta-oxidation system consists of peroxisome proliferator-activated receptor alpha (PPARalpha)-inducible pathway capable of catalyzing straight-chain acyl-CoAs and a second noninducible pathway catalyzing the oxidation of 2-methyl-branched fatty acyl-CoAs. Disruption of the inducible beta-oxidation pathway in mice at the level of fatty acyl-CoA oxidase (AOX), the first and rate-limiting enzyme, results in spontaneous peroxisome proliferation and sustained activation of PPARalpha, leading to the development of liver tumors, whereas disruptions at the level of the second enzyme of this classical pathway or of the noninducible system had no such discernible effects. We now show that mice with complete inactivation of peroxisomal beta-oxidation at the level of the second enzyme, enoyl-CoA hydratase/L-3-hydroxyacyl-CoA dehydrogenase (L-PBE) of the inducible pathway and D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl-CoA dehydrogenase (D-PBE) of the noninducible pathway (L-PBE-/-D-PBE-/-), exhibit severe growth retardation and postnatal mortality with none surviving beyond weaning. L-PBE-/-D-PBE-/- mice that survived exceptionally beyond the age of 3 weeks exhibited overexpression of PPARalpha-regulated genes in liver, despite the absence of morphological evidence of hepatic peroxisome proliferation. These studies establish that peroxisome proliferation in rodent liver is highly correlatable with the induction mostly of the L- and D-PBE genes. We conclude that disruption of peroxisomal fatty acid beta-oxidation at the level of second enzyme in mice leads to the induction of many of the PPARalpha target genes independently of peroxisome proliferation in hepatocytes, raising the possibility that intermediate metabolites of very long-chain fatty acids and peroxisomal beta-oxidation act as ligands for PPARalpha.